Hormesis: A Highly Generalizable and Reproducible Phenomenon With Important Implications for Risk Assessment

Abstract

From a comprehensive search of the literature, the hormesis phenomenon was found to occur over a wide range of chemicals, taxonomic groups, and endpoints. By use of computer searches and extensive cross-referencing, nearly 3000 potentially relevant articles were identified. Evidence of chemical and radiation hormesis was judged to have occurred in approximately 1000 of these by use of a priori criteria. These criteria included study design features (e.g., number of doses, dose range), dose-response relationship, statistical analysis, and reproducibility of results. Numerous biological endpoints were assessed, with growth responses the most prevalent, followed by metabolic effects, reproductive responses, longevity, and cancer. Hormetic responses were generally observed to be of limited magnitude with an average maximum stimulation of 30 to 60 percent over that of the controls. This maximum usually occurred 4- to 5-fold below the NOAEL for a particular endpoint. The present analysis suggests that hormesis is a reproducible and generalizable biological phenomenon and is a fundamental component of many, if not most, dose-response relationships. The relatively infrequent observation of hormesis in the literature is believed to be due primarily to experimental design considerations, especially with respect to the number and range of doses and endpoint selection. Because of regulatory considerations, most toxicologic studies have been carried out at high doses above the low-dose region where the hormesis phenomenon occurs.

The nature of nutrition: a unifying framework

“…Over recent decades, it has become apparent that hormetic responses are common, having been observed for a wide range of chemicals, organisms, and biological responses (Calabrese et al 1999;Calabrese 2005). We have argued ), however, that this unification will remain incomplete until it encompasses parallel developments in the nutritional sciences.…”

U-Shaped Dose-Responses in Biology, Toxicology, and Public Health

“…However, there are abundant examples in the toxicological and pharmacological literature indicating that overcompensation stimulation, which is observed during multidose and time interval study designs, is generally of a modest nature, usually maximally seen at 30%-60% greater than the control, with rare exceptions approaching twofold (11,17). In addition, the range of the stimulatory response would usually be limited to a factor of 10, or 20 at the most, and always contiguous with a toxic response at higher doses.…”

“…Although several significant reviews have documented the occurrence of U-shaped dose-responses in biological and toxicological systems (9,10,17,18,22), such responses have also been commonly seen in numerous pharmacological investigations (8) as well as for endpoints of considerable public health significance, including body weight and longevity (1-3, 20, 30, 36, 40, 48, 62, 63, 80-83, 89), cholesterol and longevity (28, 47), alcohol consumption and cardiovascular disease incidence (33,49,50,52,54,56), and exercise intensity/duration and immune responsive disease resistance (6,29,39,53,57,71). The occurrences of U-shaped dose-responses are thus widely and independently observed phenomena.…”

“…In fact, the principal debate over the nature of the dose-response during these early years centered around the public health issue of disinfection and whether the dose-response was based on a unimolecular mechanism leading to a linear response, or on a more threshold-like response due to interindividual variability in response to the toxin exposure (17). Nonetheless, the mundane work of Schulz became highly controversial, sparking more than a century of debate on the nature of the dose-response relationship, that is, whether the fundamental shape of the dose-response is linear, threshold, or biphasic (e.g.…”

Cardioprotection by Hormetic Responses to Aldehyde

“…4 These bidirectional dose -response relationships of treatments that are beneficial at low levels but noxious at higher levels are referred to as "hormesis". 5 In the fields of toxicology, pharmacology, radiation biology, and medicine, the significance of the biological effects of low-level exposure to various agents has attracted considerable attention. Stress response hormesis refers to the induction, by stressors, of an adaptive response that results in a general increase in stress resistance.…”